Piperidine compounds and process of making same



Patented Nov. 1, 1949 UNITED STATES OFFICE PIPERIDINE COMPOUNDS ANDPROCESS OF MAKING SAME No Drawing. Application May 9, 1944, Serial No.534,800. In Switzerland June 25, 1943 7 Claims. 1

The object of the present invention is a process of preparing4-aryl-piperidine-4-carboxylic acid nitriles, and the correspondingesters, amides and ketones.

These l-aryl-piperidines are obtained by causing a-arylatedtertiary-y-amino-butyric acid nitriles to react with reactive esters ofalkylene- 1:2-diols in the presence of acid binding agents in one ormore steps, if desired, converting the nitrile group in the4-aryl-piperidine-4-carboxylic acid nitriles thus obtained into an esteror amide group, and, if desired, splitting off radicals which aresuitable for being eliminated and are attached to the cyclic nitrogen,at any phase of the reaction.

As starting products there are used, therefore, a-arylated tertiary-'-amino-butyric acid nitriles, in which the aryl group may berepresented, e. g. by a substituted or unsubstituted phenyl or naphthylgroup, the substituents being in any position. The aliphatic radical canbe straight or branched or even arranged as part of a ring. For examplethe following compounds can be used: a-IJhGIlYlv-(methyl-benzyl-amino)-butyric acid nitrile, phenyl-v-(dimethylor diethyl-amino)-butyric acidnitrile, a-(benzylhydroxyor acylhydroxyphenyl) w- (methyl-benzyl-amino)-butyric acid nitriles, a- (o-anisyl-v- (methyl-diphenylmethylamino)-butyric acid nitrile, a-phenyl-v-(methylbenzyl-amino)-valeric acidnitrile, e-naphthyl- -(dimethyl-amino) -butyric acid nitrile oraphenyl-a-lo-(methyl benzyl amino) cyclohexyll-acetic acid nitrile. Theabove mentioned starting products are in some instances known or can beobtained in the usual manner.

For the reaction with the above nitriles the following substances, forexample, may be used: ethylene dibromide, ethylene chloro-bromide,ethylene-diiodide, propylene 1:2 dibromide,propylene-1:Z-chloro-bromide, butylene-1:2- or 2:3-dibromide, 1 2dibromo-cyclo-hexane, (3- chloro-ethanol-p-toluene sulfonic acid ester,glycol-di-p-toluene sulphonic acid ester or propane-l :2-dio1-di-methanesulp-honic acid-ester.

The reaction itself is carried out in the presence of acid bindingagents. For this purpose the following can be used: sodium, potassium,lithium calcium, as such or in the form of their alcoholates, amides orhydrocarbons as, e. g., potassium-tertiary butylate, potassium-tertiaryamylate, sodium amide, butyl-lithium, phenylsodium or phenyl-lithium. Itis advantageous to use inert solvents such as, e. g. ether, benzene,toluene, xylene or hexane and to work in the presence of indifierentgases such as nitrogen. According to the reactivity of the components,the reaction is carried out by cooling, at ordinary temperature or evenby heating. It is possible to form the ring in one or more steps.

The nitrile group of the compounds thus obtained may be converted inknown manner into an ester group. The nitrile group can also beconverted into an amide group in known manner directly or afterformation of the carboxyl group.

The piperidines obtained contain a quaternary nitrogen atom. They can beconverted into piperidines with tertiary nitrogen, for example, bysplitting off alkyl halide by heating. The conversion is also efiectedeasily if there is as a radical attached to the nitrogen, e. g., amono-, dior tri-aryl methyl group which can be removed by, among others,the help of catalytic active hydrogen or by treatment with, e. g, acidsor by heating. This conversion can moreover be carried out at anydesirable phase of the reaction.

The process is further elucidated by formulae on the basis of thefollowing example:

CH2 CH2 Ila C 3I I CH2-CtH5 (1H3 III IV \.J

CuHsC-C O O R CH2 CH2 CH2 CH2 v1 R=substituted and unsubstitutedhydrocarbon. radicalsv 3 According to the present process a large numberof piperidine compounds can be obtained. As a result of the considerablepossibilities of variation, numerous new compounds are accessible in.

Reference is made to our related copending' applications Serial N 0.530,742, filed April 12, 1944, now Patent 2,486,792, and Serial No.592,535, filed '7 1-945,-now Patent 2,486,794..

Example 1" 5218 parts of a-phen'yl-y-(methyl-benzyl-ami- A no) -butyricacid nitrile ('Bi 1?. :1 mm. 153-155 C'., prepa-Tedfrom benzyl cyanideand fl-chloroethyl rnethyl benzyl amine in the presence of sodium amide)in 200-parts= of ether are added" drop by." drop while stirrin to Id"parts of powdered sofdlumi amide: which. is suspended under nitrogen inzoolparts oif ether; When the reaction is complete the mixtureisstirredfor. an hour, then 300 parts ofi other are: added, thewholeis cooledwith anduioi parts of ethylenedibromide are added. P

Stirring is then carried. out again for an hour under-ice coolingioranother hour at room temper-ature and. for 4 to hours by heating to 40C. A thick suspension of salts is formed. This is decomposed with water.and aqueous hydrobromi'c acid is added until the acid reaction occurs.The I :'1-methyl-b'enzy1-4:4-phenyl cyanopiperidinium bromide formed,which is difficultly soluble in water, is precipitated and is isolatedby suction and washing with ether and water.

It still contains some hydrobromide of the starting product as well asother by-products. For purification the crude bromide is dissolved inthe just necessary quantity of boiling water, soda solution is added andthe mixture is allowed to cool. The thick mass isthoroughly shaken withether which. absorbs the non-quaternary bases. After suction filteringand washing with water and ether the remaining salt is recrystallized mmthe fourfold quantity of boiling water.

Thus' agood yield of the. pure 1:1-methyl-ben'zyl-= 4:4phleny1-cyano-piperidinium-bromide is obtained in two crystalline forms,as glossy flakes and as white aggregates, which cannot be converted intoeach other and probably represent cis-trans-isomers. The melting pointof both bromides is not sharp and lies at about 245 to 260 C.

If the bromide is shaken up in aqueous alcoholic solution with hydrogenand palladium black, 1-methyl-4:4-phenyl-cyano-piperidine is formedalmost quantitatively from both crystalline forms by cleavage oftoluene. The l-methyl-4z4e hen- 4 tained which can be converted,.withthe help of, e. g., potassium-tertiary butylatainto1:1-methyl-benzyl-4z4-phenyl cyano piperidinium bromide. The Compound nois also obtained if, by using this method, one starts fromethyleneb-romohydrin instead of ethylene-dibromide and the-hydroxylgroup in the intermediate product obtained is replaced by bromine.

Example 2 Aso1ution-.of.i5'2I8 parts of a-phenyl- (methyl-benzyl-amino)butyric acid nitrile in 200 parts of ether is: added drop by drop to 10parts of powdered sodium amide in 200 parts of ether.

- After stirring for 1 hour, a solution of 50 partspropylene-lzZ-dibromide in parts of ether is added. The ether slowlyreaches its boilin point'whichis maintained for 2" hoursby externalheat. In this reaction only sodium. bromide is precipitated and noquaternary salt. On decompositionv with Water an etheral and an aqueouslayer are obtained which are easily separated. After evaporation of" theether an" oil" remains which after prolonged heating on the Water'b'athbecomes solid and insoluble in ether. Therefore the formation of thering of the quaternary'bromide occurs only after applying, considerableheat. The product is tritura'ted with. ether, filtered with suction andthus the lzl-m'ethylbenzyl-2-methyl-4 4-phenyl-cyanopiperidinium bromideis obtained; The product is dissolved without further purification in.the tenfold quantity of alcohol. of 50 per cent strength. and after theaddition of about 2' per cent of aplatinum catalyzer' shaken up withhydrogen. When no more hydrogen is absorbed, the whole is filtered withsuction, a greater part of the liquid is evaporated and the residue isrendered alkaline and extracted with ether. on evaporation the etherleaves behind an oil, which boils under a pressure of 0.07 mm. at 1.07to IIO' C. This is the 1:2 dim'ethyl-4:4-phenyl cyan'o pi'peri'dine; Itcan be saponified and e'sterified according to known methods wherebywith the use of ethyl alcohol l 2 -dimethyl-4 :4-phenylcarbethoxy-piperidine is obtained which forms an oil boiling at1'05"-1'08'C. under a pressure of0.15 mm.

As starting product a-(in-nitro-p'henylT-v- (methyl-benzyl-amino)-butyric acid nitrile, e. g., can also be used and the nitro' groupinthe resulting compounds converted in usual manner into an arnino-- ora hydroxy group.

The 1-:2"-dimethyl-4-: 4 -phenyl'-cyano-piperidine obtained c'anfurtherbe converted in known manner into the 1':2-dimethyl-4-phenyl-piperidihe-4-carb'oxylic acid amide by partial saponi'fication. For the manufactureof amides the obtained nitrile canalso be completely saponifi'ed, theacid thus obtained can be converted into" the acid chloride by treatmentfor example withthionyl chloride, and the acid chloride reacted withammonia or amines. Thus, from the corresponding acid chloride anddiethylamine there is obtained 1'22dimethyl-4-phenyl-piperidine-4-carboxyli'c. acid amide.

These amides can also be obtained by converting the above obtained1:l-methyl-benzyl-2- methyl-4:4-phenyl-cyano-piperidihium bromide intothe amides and subsequentlysplittingoifthe benzyl. group.

In an. analogousv manner the fol-lowing compounds. may be produced: 1':.2:3-t'riaIkyl-4:4- phenyl-carbalkoXy-piperidines, such as. L12 :3-tri-methyl-4:4-phenylrcarbethoxy-piperidine. or 1 alkyl 4 4phenyl.-carbalkoxy -decal'1yd'1:o

quinolines, such as 1-methyl-4:4-phenyl carbethoxy-decahydroquinoline.

Example 3 Asolution of 65 parts of a-phenyl-y- (diethyl-amino)butyricacid nitrile in 200 parts of absolute ether is added drop by drop toMparts of powdered sodium amide in 300 parts of ether. After an hoursstirring 300 parts of ether are added, the mixture cooled with ice andthen 60 parts of ethylene-dibromide added. Stirring is carried out forone hour at ice temperature, for another hour at room temperature andfour to six hours at the boiling temperature of the ether. The veryconsistent reaction mass is separated by filtration with suction, Washedwith ether and dried. 125 parts of a white salt mixture are obtainedwhich consists, besides sodium bromide, chiefly of 1:1- diethyl-ei-phenyl-cyano-piperidinium bromide. The latter is readily soluble inwater. By treating with alcohol, the insoluble sodium bromide containedtherein can be eliminated. If the piperidinium bromide or the hydroxidewhich can be prepared from it, is heated in the vacuum, there isproduced by cleavage of ethyl bromide or ethyl alcohol, respectively,the 1-ethyl-414- phenyl-cyano-piperidine which is an oil boiling at 110to 112 C. under a pressure 0.05 mm. It can be saponified and esterifiedin known manner.

If in one or another of the above examples there are used as startingmaterials derivatives containing in their aryl nucleus alkyl-hydroxyoraralkyl-hydroxy-groups, the compounds with free phenolic hydroxyl groupscan easily be obtained from the resulting reaction products in knownmanner by hydrolysis or hydrogenation, respectively.

What we claim is:

1. In a process for the manufacture of a 4- aryl-piperidine, the step ofreacting an u-phenyl tertiary 'y-amino-butyric acid nitrile of theformula wherein R1 is lower alkyl and R2 is a member selected from thegroup consisting of lower alkyl and aralkyl, with ana1kylene-1:2-dihalide of the formula hal -CHE;

hal- HR.

wherein hal is a halogen atom, R3 and R4 are members selected from thegroup consisting of hydrogen atoms and lower alkyl, in the presence of adehydrohalogenating agent, whereby a 4:4-phenyl-cyano-piperidinium-halide is formed of the formula wherein R1--R4and hal have the same meaning as above.

2. In a process according to claim 1, the additional step of hydrolyzingthe resultant product whereby the nitrile group is converted into acarboxyl group.

3. In a process for the manufacture of a 4- phenyl-piperidine, the stepof reacting a-phenylv-(methyl-benzyl-amino) -butyric acid nitrile of theformula OHa CHz-CaHa is formed.

4. In a process according to claim 3, the add tional steps ofhydrolyzing the resultant product whereby the nitrile group is convertedinto a carboxyl group and then splitting off the benzyl radical bytreating the product with catalytically active hydrogen.

5. In a process according to claim 3, the additional steps ofhydrolyzing and esterifying the resultant product whereby the nitrilegroup is converted into an ester group and then splitting on the benzylradical by treating the product with catalytically active hydrogen.

6. In a process according to claim 3, the additional steps ofhydrolyzing the resultant product whereby the nitrile group is convertedinto a carboxyl group and then splitting off the benzyl radical by atreatment with hydrogen in the presence of palladium black.

'7. In a process according to claim 3, the additional steps ofhydrolyzing and esterifying the resultant product whereby the nitrilegroup is converted into an ester group and thensplitting off the benzylradical by a treatment with hydrogen in the presence of palladium black.

KARL MIESCHER. HANS KAEGI.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date 2,167,351 Eisleb July 25, 1939FOREIGN PATENTS Number Country Date 501,135 Great Britain 1939 OTHERREFERENCES Archiv. for Exp. Path. Pharm, vol. 196, Pp. 127-129.

J. Amer. Chem. 806., vol. 65, pp. 2093-2095.

will;

Certificate of Correction November 1, 1949 Patent No. 2,486,793

' KARL MIESCHER ET AL. It is hereby certified that errors appear in theprinted specification of the above numbered patent requiring correctionas follows:

Column 1, lines 3 and 4, for esters, amides and ketones read esters andamides; lithium insert a comma; column 5, line 1, after phenyl line 48,after the Word insert a hyphen;

and that the said Letters Patent should be read with these correctionstherein that d of the case in the Patent Oflice.

the same may conform to the recor sealed this 7th day of March, A. D.1950.

Signed and lm l THOMAS F. MURPHY,

Assistant Commissioner of Patents.

